Prostate cancer is the second most common cancer in men, accounting for 70% of all cancer cases in the developed world. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer (CRPC). Androgen deprivation therapy is an established treatment for advanced prostate cancer. However, many men eventually fail this therapy and die of CRPC. Recent research attributes the progression of CRPC to neuroendocrine trans-differentiation (NEtD) of cancerous prostate cells. However, the mechanism through which NEtD occurs in prostate cancer remains unclear. Clinical observations have suggested that NEtD correlates with cancer progression and poor prognosis.
The presence of olfactory receptor OR51E2, also known as Prostate Specific G-protein Receptor (PSGR), in prostate cancer is well documented, but its function is not completely understood. This G protein-coupled receptor (GPCR) is expressed in healthy prostate tissue and is significantly over-expressed in prostate cancer. Furthermore, increased expression of OR51E2/PSGR in CRPC has been documented, but its role and function in disease progression is currently unknown. Xu et al. demonstrated an increased abundance of OR51E2 in LNCaP cells during androgen deprivation. Androgen deprivation results in G0-G1 arrest, cellular senescence, an NE cell-like phenotype, and development of highly aggressive clones. (Xu et al. (2000) Cancer Research 60:6568-72).
Furthermore, epidemiological, histopathological, and genetic studies have shown that chronic infection and inflammation are important in prostate carcinogenesis. Many agents can induce inflammation of the prostate. One such agent is Propionibacterium acnes, which is predominantly a skin commensal bacterium, but is also found in the oral cavity and gastrointestinal tract. P. acnes is involved in the pathogenesis of acne and is often recognized as an opportunistic pathogen and the cause of chronic post-operative prosthetic joint infections, osteomyelitis, and endocarditis. P. acnes infection induces a strong inflammatory response and IL-6, IL-8, and GM-CSF secretion. P. acnes produce propionic acid (PA), which causes acute and chronic prostatitis. Chronic infection produces a constant supply of PA, which acts as an agonist for OR51E2. Short-term activation of OR51E2 in prostate epithelial cells (RWPE-2) causes an inflammatory reaction, while prolonged/chronic activation may facilitate NEtD, thus contributing to a more aggressive phenotype.
Currently identified agonists for OR51E2 include propionic acid, acetic acid, androstenone derivatives, and beta-ionone. The only known antagonist is alpha-ionone, an aroma compound. However, it is unknown whether any of these ligands have an active role in prostate cancer pathogenesis.
The incidence of prostate cancer is increasing worldwide and there is an urgent need for better diagnostic strategies to distinguish between indolent and aggressive tumors, and to develop more efficacious treatment options for highly aggressive tumors. The results described herein demonstrate that chronic agonist-mediated activation of the OR51E2/PSGR receptor can turn this receptor into an oncogene and thereby facilitate cellular progression and transformation resulting in NEtD, a characteristic phenotype of CRCP. Additionally, the ligands described herein represent potential novel anti-cancer and diagnostic agents. Results from the studies of the present invention assist in defining the role and function of OR51E2/PSGR. In particular, the identification of novel metabolite-agonists provides important molecular and biochemical insights into the biological role of this receptor in prostate tissue physiology and pathophysiology. Finally, the inducement of NEtD by prolonged activation of OR51E2 by PA, a product of P. acnes fermentation, elucidates a causal link between chronic inflammation and NED in prostate cancer.